权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Inflammasome and Gasdermin Signaling Networks for Regulation of Pyroptosis and Cytokine Release

用于调节焦亡和细胞因子释放的炎性体和 Gasdermin 信号网络

基本信息

批准号：
10654563
负责人：
GEORGE R DUBYAK
金额：
$ 188.67万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-24 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654563
关键词：
Acute Alzheimer&apos s Disease Amyloid Apoptosis Apoptotic Autophagocytosis Biochemical Biochemistry CASP1 gene CASP3 gene CASP8 gene CASP9 gene Caspase Categories Cell Death Cell Lineage Cell membrane Cell physiology Cells Cellular biology Chaperone Protein Interaction Chronic Compensation Complex Crohn&apos s disease Cytolysis DNA Disease Disease model Dissociation Dysmyelopoietic Syndromes Effector Cell Elements Epithelial Cells Extracellular Space Familial Mediterranean Fever Functional disorder Genetic Goals Golgi Apparatus Immune Immune response Immunologics Infection Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Innate Immune Response Interleukin-1 beta Investigation Link Literature Lytic Macrophage Mediating Mediator Membrane Molecular Multiple Sclerosis Mus Myeloid Cells Myocardial Infarction N-terminal Necrosis Nonlytic Pathogenesis Pathogenicity Pathway interactions Peptide Hydrolases Peptide Signal Sequences Population Production Proteins Publishing Reagent Regulation Reporting Secretory Vesicles Signal Transduction Source Sterility Stimulus T-Lymphocyte Testing Tissues Ulcerative Colitis VDAC1 gene cell killing cell type cytokine extracellular gastrointestinal granulocyte gut inflammation human disease intestinal epithelium microbial mouse model neutrophil novel programs response restraint structural biology structural determinants trafficking

项目摘要

OVERALL PROGRAM PROJECT: ABSTRACT Cell death pathways have historically been characterized by the proteases that become activated during cell fate decisions. Apoptosis has been defined by initiator and effector caspase activation and, largely due to the reagents available; cell death decisions were initially thought to be binary – caspase-dependent (apoptosis) or caspase-independent (all others). Much like other binary distinctions – like Th1 versus Th2 T cells or M1 versus M2 macrophages, which have undergone substantial expansion in the past decade, cell death decisions and their consequences are now recognized to be much more variables. In fact, even the mechanisms of cell death have been refined. They are no longer categorized by the proteases which activate the cascades but rather, by the effector mechanism. Necroptotic cell death is caused by activation of the pore-forming protein, MLKL. Secondary necrosis is caused by activation of the pore-forming protein, DFNA5 (Gasdermin E/GSDME), and pyroptosis is caused by activation of the pore-forming protein, Gasdermin D (GSDMD) This last category of cell death - pyroptosis - is one of the most immunologically important forms of cell death. Not only does pyroptosis kill the cell, but also GSDMD activation allows the release of IL-1β. This cytokine is among the most important in acute and chronic inflammation. Its secretion is implicated in rare genetic inflammatory diseases such as Familial Mediterranean Fever as well as more common diseases such as myocardial infarction, Alzheimer's disease, Crohn's disease and Ulcerative Colitis, Multiple Sclerosis and many others. With the discovery of the inflammasome in 2002 and its subsequent study, it became clear that the amyloid-like activation of these inflammasome complexes drove pro-IL-1β cleavage and IL-1β release from the cell, but also pyroptosis. Missing from this biochemistry, though, was the cell biology underlying IL-1β release. How is IL- 1β recognized by caspases and other proteases? If IL-1β is not released through a secretory ER-Golgi mechanism, how is trafficked out of the cell? How is this release coordinated with pyroptosis and other regulated cell death pathways that are operative in different populations of immune effector cells. This Program Project aims to utilize cell physiology, biochemistry, structural biology, and mouse and human disease models to unravel these important questions.

总体项目：摘要细胞死亡途径历来以蛋白酶为特征，在决定细胞命运的过程中被激活。细胞凋亡由启动子和效应子半胱天冬酶定义激活，主要是由于可用的试剂;细胞死亡决定最初被认为是是二元的-半胱天冬酶依赖性（凋亡）或半胱天冬酶非依赖性（所有其他）。很像其他二元区别-如Th 1与Th 2 T细胞或M1与M2巨噬细胞，在过去的十年里经历了实质性的扩张，细胞死亡的决定及其结果现在被认为是更多的变量。事实上，即使是细胞死亡已经被完善。它们不再被分类为激活蛋白酶而是通过效应器机制。坏死性细胞死亡是由孔形成蛋白MLKL的活化。继发性坏死是由于激活了孔形成蛋白，DFNA 5（Gasdermin E/GSDME），和焦亡是由激活成孔蛋白Gasdermin D（GSDMD）这是最后一类细胞死亡-细胞凋亡- 是免疫学上最重要的细胞死亡形式之一。尸体自燃不仅能杀死细胞，而且GSDMD激活允许IL-1β的释放。这种细胞因子是最常见的在急性和慢性炎症中很重要。它的分泌物与罕见的遗传炎症性疾病，如家族性地中海热以及更常见的疾病如心肌梗塞、阿尔茨海默病、克罗恩病和溃疡性结肠炎，多发性硬化症和许多其他疾病。随着2002年炎性小体的发现及其随后的研究表明，这些炎性小体的淀粉样激活复合物驱动IL-1β前体裂解和IL-1β从细胞中释放，但也驱动细胞凋亡。然而，这种生物化学中缺少的是IL-1β释放背后的细胞生物学。怎么样- 1β被半胱天冬酶和其他蛋白酶识别？如果IL-1β不是通过分泌型 ER-高尔基体机制，是如何被贩运出细胞的？这一版本如何与细胞凋亡和其他调节性细胞死亡途径，这些途径在不同人群中起作用，免疫效应细胞本计划项目旨在利用细胞生理学，生物化学，结构生物学，以及小鼠和人类疾病模型来解开这些重要的问题。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Ras GTPase-activating-like protein IQGAP1 bridges Gasdermin D to the ESCRT system to promote IL-1β release via exosomes.

DOI：
10.15252/embj.2022110780
发表时间：
2023-01-04
期刊：
EMBO JOURNAL
影响因子：
11.4
作者：
Liao, Yun;Chen, Xing;Miller-Little, William;Wang, Han;Willard, Belinda;Bulek, Katarzyna;Zhao, Junjie;Li, Xiaoxia
通讯作者：
Li, Xiaoxia

The synthetic oleanane triterpenoid CDDO-2P-Im binds GRP78/BiP to induce unfolded protein response-mediated apoptosis in myeloma.

DOI：
10.1002/1878-0261.13447
发表时间：
2023-12
期刊：
MOLECULAR ONCOLOGY
影响因子：
6.6
作者：
Luo, George;Aldridge, Kristin;Chen, Toby;Aslot, Vivek;Kim, Byung-Gyu;Han, Eun Hyang;Singh, Neelima;Li, Sai;Xiao, Tsan Sam;Sporn, Michael B.;Letterio, John J.
通讯作者：
Letterio, John J.

Partners with a killer: Metabolic signaling promotes inflammatory cell death.